Preoperative paroxysmal atrial fibrillation predicts high cardiovascular mortality in patients undergoing surgical aortic valve replacement with a bioprosthesis: CAREAVR study

Abstract Background Preoperative permanent atrial fibrillation (AF) is associated with impaired outcome after surgical aortic valve replacement (SAVR). The impact of preoperative paroxysmal AF, however, has remained elusive. Purpose We assessed the impact of preoperative paroxysmal AF on outcome in patients undergoing SAVR with bioprosthesis. Methods A total of 666 patients undergoing isolated AVR with a bioprosthesis were included. Survival data was obtained from the national registry Statistics Finland. Patients were divided into three groups according to the preoperative rhythm: sinus rhythm (n = 502), paroxysmal AF (n = 90), and permanent AF (n = 74). Results Patients in the sinus rhythm and paroxysmal AF groups did not differ with respect to age (P = .484), gender (P = .402) or CHA2DS2‐VASc score (P = .333). At 12‐month follow‐up, AF was present in 6.2% of sinus rhythm patients and in 42.4% of paroxysmal AF patients (P < .001). During follow‐up, incidence of fatal strokes in the paroxysmal AF group was higher compared to sinus rhythm group (1.9 vs 0.4 per 100 patient‐years, HR 4.4 95% Cl 1.8‐11.0, P = .001). Cardiovascular mortality was higher in the paroxysmal AF group than in the sinus rhythm group (5.0 vs 3.0 per 100 patient‐years, HR 1.70 95% CI 1.05‐2.76, P = .03) and equal to patients in the permanent AF (5.0 per 100 patient‐years). Conclusion Patients undergoing SAVR with bioprosthesis and history of paroxysmal AF had higher risk of developing permanent AF, cardiovascular mortality and incidence of fatal strokes compared to patients with preoperative sinus rhythm. Life‐long anticoagulation should be considered in patients with a history of preoperative paroxysmal AF.

Conclusion: Patients undergoing SAVR with bioprosthesis and history of paroxysmal AF had higher risk of developing permanent AF, cardiovascular mortality and incidence of fatal strokes compared to patients with preoperative sinus rhythm. Life-long anticoagulation should be considered in patients with a history of preoperative paroxysmal AF. The prevalence of AF is 0.5% to 1% in general population, but increases with aging and about 10% of octogenarians have AF. [1][2][3][4] Permanent AF is associated with increased mortality and risk of thromboembolic complications. 5 In particular, the risk is increased in AF patients with comorbidities such as hypertension, heart failure, coronary artery disease, and valvular heart diseases. 4,[6][7][8][9] Thus, there is still some debate whether AF is an independent predictor of adverse prognosis or whether the worse prognosis among AF patients rather reflects increased age and associated comorbidities. In addition, it is controversial whether the risk related to AF is equal in patients with paroxysmal and permanent AF. In recent guidelines the indications for permanent oral anticoagulation are the same in different types of AF. 10 Several studies have demonstrated that preoperative permanent AF is a predictor of impaired outcome after adult cardiac surgery and transcatheter aortic valve implantation (TAVI). 7,8,[10][11][12][13][14][15] However, the impact of preoperative paroxysmal AF in these patients is less well known. Namely, earlier studies included only patients with permanent AF 2,13,16 or patients with paroxysmal and permanent AF, were pooled. 4,14,17 Thus, the prognostic significance of paroxysmal AF has remained elusive.
The aim of this multicenter study was to evaluate the impact of preoperative paroxysmal and permanent AF on mortality and morbidity after isolated bioprosthetic SAVR in comparison to patients in sinus rhythm.

| METHODS
The CAREAVR is a Finnish multicenter, retrospective registry (ClinicalTrials.gov Identifier: NCT02626871) evaluating the incidence of AF, thromboembolic complications and bleeding events in patients undergoing isolated SAVR with bioprosthesis.

| Statistical analysis
Continuous variables were reported as mean ± SD if normally distributed, and as median (inter-quartile range) if they were skewed.

| RESULTS
A total of 666 patients undergoing isolated SAVR with a bioprosthesis were included in the final analysis. Patients were divided into three groups according to the history of preoperative rhythm: sinus rhythm (n = 502), paroxysmal AF (n = 90), and permanent AF (n = 74). The mean follow-up time was 4.9 ± 2.7 years.
In the baseline clinical characteristics the paroxysmal AF group had larger left atrium diameter (P < .001), lower estimated glomerular filtration rate (eGFR) (P = .014), higher INR (P < .001), and they were more often on warfarin therapy (P < .001) compared to the sinus rhythm group (Table 1). With respect to other baseline characteristics, including age, sex, and CHA 2 DS 2 -VASc score, patients in the paroxysmal AF group and sinus rhythm group did not differ.

| Late outcome
All-cause mortality in the paroxysmal AF group (7.2 per 100 patientyears at risk) tended to be higher compared to the sinus rhythm group (4.9 per 100 patient-years) (HR 1.5, 95% CI 1.0-2.2, P = .057) (  Figure 1A). All-cause mortality in the permanent AF group (7.1 per 100 patient-years) also tended to be higher than in the sinus rhythm  (Figures 1C and 2). Cardiovascular mortality was also higher in the permanent AF group (5.0 per 100 patient-years) than in the sinus rhythm group (HR 1.8 95% Cl 1.0-3.1, P = .039). This was mainly due to high rate of fatal bleeds 1.6 per 100 patient-years compared to 0.3 per 100 patient-years in the sinus rhythm patients (HR 5.2 95% Cl 1.6-16.2, P = .005 ( Figure 1D).
Logistic regression analysis was also performed to adjust for the differences in preoperative clinical characteristics (eGFR and left atrium size) between the sinus rhythm and paroxysmal AF groups. After adjustment of these, paroxysmal AF remained as an independent predictor of fatal stoke (HR 3.4, 95% CI 1.

| DISCUSSION
The main findings of the study were that patients with preoperative paroxysmal AF undergoing SAVR had high risk of developing permanent AF during follow-up. In addition, they were at higher risk of cardiovascular Importantly, cardiovascular mortality in the paroxysmal AF patients was significantly higher compared to those in sinus rhythm and of same magnitude as in patients with permanent AF. This was somewhat surprising since as comes to the preoperative clinical characteristics patients with paroxysmal AF were well matched with their counterparts in sinus rhythm. These two groups did not differ with respect cardiovascular risk factors such as cardiac function, CHA 2 DS 2 -VASc score or other comorbidities, which are significant predictors of mortality and morbidity in cardiac patients and patients with AF as well as also patient with bioprosthesis. 24 Paroxysmal AF group had lower eGFR and larger left atrium diameter. However, after adjustment of these, paroxysmal AF remained as an independent predictor of fatal strokes.
In the present study fatal strokes were primarily responsible for the high cardiovascular mortality in the paroxysmal AF patients with 4-fold risk compared to the sinus rhythm patients and 1.5-fold compared to permanent AF patients. On the other hand, there was no significant difference between patients with paroxysmal AF and sinus rhythm with respect to cardiac deaths or non-cardiac deaths. Stroke and other thromboembolic complications in AF patients are often of embolic origin. 25 Correspondingly, our results suggest that AF resulting in cardio-embolism rather than heart failure or sudden death were responsible for the increased mortality among patients with paroxysmal AF. Our results are also in line with a Danish study including 15 000 AF patients with heart failure. 12 They reported that patients with paroxysmal AF had higher risk of stroke than patients with sinus rhythm or persistent or permanent AF. These findings suggest that in spite of an increased risk of thromboembolism, anticoagulation therapy has not been adopted properly in patients with paroxysmal AF undergoing SAVR with a bioprosthesis.
What merits to be addressed is that only 14% of the paroxysmal AF group patients suffering from fatal stroke and prescribed OAC had INR preceding the event within the target range. Further, in the permanent AF group none had INR within the therapeutic range at the time of bleeding event. These suggest that in most cases the events, whether stroke or bleeding were related to poor anticoagulation control. This is in accordance with a previous report in patients with nonvalvular AF. In AF patients on OAC and suffering from stroke, INR at the time of event was outside the therapeutic target in more than 50% of patients. 23 Permanent AF is a well-known predictor of adverse outcomes in patients scheduled for SAVR (14). However, to our best knowledge there are no earlier studies addressing the question of paroxysmal AF in patients undergoing SAVR with a bioprosthesis. A closest counterpart to our study is a recent paper by Shaul et al. 8 They evaluated the differential impact of paroxysmal and permanent AF) on the outcome after TAVI. In contrast to our findings, they reported that the risk of death or stroke at 2 years was similar in patients with sinus rhythm (16%) and paroxysmal AF (15%), whereas it was significantly higher among patients with permanent AF (38%). Such differences might be explained by a different risk profile in TAVI patients compared to patients undergoing SAVR with a bioprosthesis as well as by the fact that temporary anticoagulation is not used after TAVI. 26 Ngaage et al 11

| Strengths and limitations
This study has several methodological strengths. The data were collected from electronic patient records and hospital database in which the data are stored prospectively in predefined form. A validated, structured case report form was used. A quality control monitoring of the data was performed by a clinical research organization. The patient population comes from the hospital regional catchment area where all cerebrovascular events are treated exclusively at the participating centers. All patients undergoing SAVR were scheduled for follow-up visits at 3 and 12 months. Thus, the follow-up data were available from almost all patients. A major strength of our study is also that in Finland each patient has a national identification code. This allows the follow-up and identification of patients' date and cause of death through the country. Nevertheless, the retrospective set-up carries also some limitations. It does not allow characterization of the study populations as accurately as in a prospective trial. An obvious limitation is that the presence of AF during follow-up was based on 12-lead ECG recorded during routine 3-and 12-month follow-up visits or in case of symptomatic AF episodes whereas no routine Holter recordings were performed. Thus, it is likely that some episodes of asymptomatic paroxysmal AF were missed.

| CONCLUSIONS
In patients scheduled for SAVR with bioprosthesis, paroxysmal AF was associated with increased mortality-particularly increased risk of fatal strokes-and higher risk of developing permanent AF compared to those with a history of sinus rhythm. Life-long anticoagulation should be considered in these patients after the surgery.